Unraveling the Tapestry: Linkages between Maternal Metabolic Conditions and

Neurodevelopmental Disorders in Progeny, Delving into the Intricate Threads of

Obstetric and Neonatal Complications
Dr. Sadaf Nawaz1, Dr. Noman Akbar2, Dr Faizan Hameed3, Nasira Shaheen4, Dr.Babar Sultan Khaghan5,
Amit Kumar Thakur6*, Dr. Saira Tasawar7, Dr. Shumaila Ashraf8
1
Child Specialist Institute Combined Military Hospital Gujranwala.
2
Pathologist Specialist Institute Combined Military Hospital Gujranwala.
3
Social Security Hospital Sheikhupura.
4
Bahria International Hospital Phase 8 Rawalpindi.
5
Associate professor of General Surgery Ayub Teaching Hospital Abbottabad.
6
House Officer Institute BVH, Bahawalpur.
7
Post Graduate Resident, Pediatrics Medicine Bahawal Victoria Hospital Bahawalpur.
8
PGR PEADS MEDICINE, MAYO HOSPITAL LAHORE

Abstract
Studies have shown that if a mother contracts a viral or bacterial infection during the early stages of pregnancy,
there is a significantly higher likelihood that her unborn child would have a neurodevelopmental disorder
(NDD) such as schizophrenia, autism, or ADHD. However, there is limited knowledge regarding the impact of
immunological activity during early life on the development of brain systems. It is believed that the mother's
immune response may interfere with crucial brain activities necessary for the normal development of the fetus
and newborn, leading to distinct behaviors observed in individuals with neurodevelopmental disorders (NDD).
Maternal immune activation (MIA) in rodent models has yielded valuable knowledge regarding the brain
abnormalities that arise as a consequence of MIA. This review begins by doing a comprehensive examination of
human epidemiological data. Its primary objective is to investigate the correlation between various types of
maternal immune activation (MIA) and the occurrence of developmental abnormalities in kids that are not
related to household environments. Subsequently, we will examine prevalent rodent MIA models and assess
their concordance with human data. The study also considers additional variables that influence the likelihood of
neurodevelopmental disorders (NDDs) in individuals with MIA. It suggests that future research should
incorporate these aspects for further analysis. The elements that influence the diversity in neurological and
behavioral responses to MIA include the offspring's sex, the timing of the immunological challenge, genetics,
parental age, the gut microbiome, prenatal stress, and placental buffering.

Introduction
According to Abdallah et al. (2012), the occurrence of neurodevelopmental disorders (NDDs) in the United
States is 13.87%, which represents an increase of around 9.5% compared to the preceding decade. This
information is based on statistics from the Centers for Disease Control and Prevention. The main factor behind
this rise is the advancements achieved in diagnostic abilities. Albani et al. (2014) note that the occurrence of
NDDs is generally similar around the globe, but variations exist due to socioeconomic factors, levels of
awareness, and diagnostic methods in different nations. Key epidemiological parameters associated with NDDs
encompass the age of onset, symptomatology, gender-specific prevalence rates, and the risk factors linked to
these disorders.

Zawadzka et al. (2021) found that genetic factors establish an initial risk for various non-communicable diseases
(NDDs), which is then influenced by additional factors including prenatal infections leading to maternal
immune activation (MIA). This immune activation then alters the risk for certain NDDs. MIA is distinguished
by increased levels of immune-related chemicals, such as cytokines and chemokines, and is typically
investigated in relation to maternal exposure to immunogens during pregnancy. Rat models are extensively
utilized in the field of animal testing to simulate Maternal Immune Activation (MIA). This is achieved either
direct infection or stimulation of the immune system. The purpose is to investigate how immune activation
during pregnancy impacts brain alterations related to non-disruptive disorders. Albani et al. (2014) study states
that research on the correlation between immunological activation and brain development in the context of
neurodevelopmental disorders (NDDs) is currently ongoing.

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This review has three main objectives: (1) to assess the epidemiological evidence that supports the connection
between maternal immune activation (MIA) and the increased risk of neurodevelopmental disorders (NDDs);
(2) to provide a brief overview of the commonly used rodent models of MIA and their relevance to the study of
NDDs in humans; and (3) to explore additional factors in rodent research that should be taken into account,
including the timing and severity of infection, gender-based variations in susceptibility and symptoms of NDDs,
and individual variations in response to MIA. The primary objective of this study is to examine the
epidemiological correlation between maternal immune activation (MIA) and neurodevelopmental disorders
(NDDs) in order to identify crucial elements that should be incorporated in the design of future studies involving
both humans and rodents. Employing this approach will enable scientists to accurately determine the
immunological and neurological roots of NDDs, thereby facilitating the development of tailored drugs and
treatment approaches.

Neurodevelopmental Disorders
The term "neurodevelopmental disorders" (NDDs), introduced in the DSM-5, encompasses a variety of
conditions that hinder development in areas such as language, physical skills, social interaction, and learning.
The occurrence of these disorders is often linked to medical, environmental, or genetic factors that occur early in
childhood (Morris-Rosendahl & Crocq, 2020). Notable neurodevelopmental disorders (NDDs) include
intellectual disability (ID), autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD),
and communication difficulties. The frequency of these disorders in boys and girls aged 3-17 in the United
States varies, exhibiting significant discrepancies (Yang et al., 2022). Although not classified as a
Neurodevelopmental Disorder (NDD) in the DSM-5, schizophrenia is believed to arise from disruptions in the
developmental process. The onset of symptoms often occurs during the latter stages of adolescence.

Individuals with various Neurodevelopmental Disorders (NDDs) may have a combination of symptoms such as
cognitive and learning difficulties, social behavior abnormalities, disrupted sleep patterns, and metabolic or
gastrointestinal problems. However, the manifestation of these symptoms is contingent upon the specific ailment
and the individual. Learning difficulties and sleep disturbances vary among conditions such as Autism Spectrum
Disorder (ASD), schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD).

The extent to which the underlying neurobiology in different neurodevelopmental disorders (NDDs) contributes
to the overlapping symptoms remains unclear. These symptoms might arise from particular neurobiological
abnormalities associated with illnesses or from general neurobiological processes, such as imbalances in the
brain's excitatory/inhibitory balance. Maternal immune activation (MIA) is believed to have a significant impact
on the development of numerous neurodevelopmental disorders (NDDs), perhaps leading to symptoms that
resemble illness-like behavior. The National Institutes of Mental Health (NIMH) implemented the Research
Domain Criteria (RDoC) framework as a reaction to the diverse and interconnected nature of symptoms. This
paradigm emphasizes a multidimensional approach to study, focusing on specific elements of diseases rather
than the disorders as a whole. This methodology, which considers many risk factors and patterns of symptom
manifestation, can assist us in understanding the variations in neurodevelopmental disorders from one case to
another.

The study acknowledges the influence of several genetic and environmental variables, including sex, parental
age, stress, diet, and pregnancy complications, in predicting the likelihood of neurodevelopmental disorders
(NDD). The subsequent sections of the study will go into a comprehensive analysis of the epidemiological data
that supports the recognition of MIA as a significant risk factor for various neurodevelopmental disorders
(NDDs).

Maternal Immune Activation And Neurodevelopmental Disorder Risk

It has been established by Zablotsky et al. (2019) that brain development and subsequent behavior in later stages
of life can be negatively impacted by environmental variables and viruses. In infants, maternal immune
activation (MIA) increases the risk of neurodevelopmental disorders (NDDs), according to epidemiological
studies. It is critical to recognize that maternal immune activation (MIA) encompasses any disruption of the
immune system that takes place in animals or humans during pregnancy. According to research conducted on
animals, the initial fortnight of neonatal development in mice is analogous to the third trimester of human fetal
growth (Vorstman et al., 2017). The critical processes of immunogenesis, apoptosis, and synaptogenesis, which
are observed in rodents during the third trimester of human brain development, occur subsequent to birth (Wang
et al., 2017).

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Cohort and case-control studies are methodologies that are utilized to examine the prevalence of
neurodevelopmental disorders (NDD) and maternal immune activation (MIA) in human subjects (Sarfraz et al.,
2023). Cohort studies involve the identification of subjects who have undergone a designated period of exposure
to an infectious agent. Following that, the likelihood of them developing a specific malady is assessed through
either retrospective or prospective methods. Case-control studies involve the identification of individuals who
are afflicted with a specific malady, followed by an examination of any potential risk factors or exposure
variables. These investigations corroborate infection rates through the utilization of self-report, serology, or
medical data. The observational nature of these studies on humans complicates the task of establishing a direct
correlation between symptoms of NDD and MIA. This emphasizes the critical nature of conducting basic
biomedical research and employing animal models in order to identify the precise molecular, cellular, or neural
circuit modifications that are responsible for the development of Neurodevelopmental Disorders (NDD) and
Maternal Immune Activation (MIA). On the contrary, the most persuasive evidence linking maternal immune
activation (MIA) to neurodevelopmental disorders (NDDs) comes from epidemiological studies examining the
effects of pathogens and environmental stressors, specifically viral and bacterial infections during pregnancy
(Ahmed et al., 2023).

Epidemiological Disease Type, Severity, Fever Response, and Therapeutic

Researchers have shown that infants whose mothers had infections when they were pregnant are more likely to
suffer from neurodevelopmental disorders (NDDs) such schizophrenia and autism spectrum disorder (ASD).
Viruses like rubella and influenza, as well as bacteria like urinary and vaginal infections, can cause these
neurodevelopmental disorders (NDDs) in pregnant women. Parasitic illnesses, especially Toxoplasmosis gondii,
have been linked to schizophrenia.

Children whose mothers contracted rubella during the first trimester of pregnancy were at a higher risk of autism
spectrum disorder (ASD), a finding that came to light during the 1960s rubella epidemic in the US. Prenatal
exposure to excessive levels of vitamin A and liver failure are two possible causes of this correlation. There is
mounting evidence that prenatal rubella exposure increases the risk of nonaffective psychosis and schizophrenia
in young adults.

Bacterial infections in the second and third trimesters of pregnancy are significantly associated with the
development of ASD and ADHD in children, according to studies. Furthermore, in situations when psychosis
runs in the family, there is a strong correlation between bacterial infections in the mother and an elevated risk of
schizophrenia in children.

Although there is a lack of clear evidence, it has been suggested that pregnant women with influenza are more
likely to develop schizophrenia. There is mounting evidence linking influenza infection during pregnancy,
especially in the second trimester, to an increased risk of schizophrenia, according to a number of studies.
However, other studies have failed to find an association between influenza during pregnancy and ASD, thus the
link is far from proven.

The risk of neurodevelopmental disorders (NDDs) and autism spectrum disorder (ASD) in children is increased
in correlation with maternal fever, making a high body temperature during pregnancy a serious concern,
according to research. This risk can be lowered by using antipyretics throughout pregnancy.

Consideration of the severity and duration of diseases and feverish responses during pregnancy is of the utmost
importance. A greater risk of developing Autism Spectrum Disorder (ASD) has been associated with longer
durations of fever and more severe diseases. Accordingly, the probability of a diagnosis of autism spectrum
disorder (ASD) or schizophrenia is significantly affected by the severity of the fever response and the degree of
infection experienced during pregnancy. When assessing the risk of neurodevelopmental disorders (NDDs) in
children, it is crucial to include the type, timing, and severity of maternal infections during pregnancy. This is
highlighted by these findings.

Expression of cytokines and chemokines throughout pregnancy

Numerous studies support Dr. Paul Patterson's hypothesis that the maternal immune response and the cytokines
it secretes into circulation may increase children's risk of neurodevelopmental disorders (NDDs) from influenza
or other infections, rather than direct fetal infection. Human epidemiological research confirms this idea after
decades. Research in California, USA, found a correlation between elevated cytokine (IL-4, IL-5), interferon
(IFN)-γ, and interleukin (IL)-4 levels in maternal serum during mid-pregnancy and increased risk of autism
spectrum disorder (ASD) in offspring after adjusting for maternal characteristics and gestational age at specimen

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collection. A Danish research found higher levels of TNF-α and TNF-β in amniotic fluid of people diagnosed
with autism spectrum disorder (ASD). Autism spectrum disorder (ASD) was also linked to higher IL-4, IL-10,
and MCP-1 levels after 1993, when autism diagnostic criteria were reevaluated.

According to Sullivan et al. (2015), high levels of pro-inflammatory cytokines such TNF-α, IL-1β, and IL-6 in
maternal blood samples at or before birth in Philadelphia, USA, were linked to mental illnesses in adult
offspring. The association was strongest in early pregnancy samples. Research in Rhode Island found a link
between elevated TNF-α and IL-8 levels in parturition samples, particularly in cases of maternal infection in the
third trimester, and increased risk of psychosis in offspring (Buka et al., 2001).

These data imply that infections activate several cytokines and chemokines. Chemokines and cytokines can
cross the placental barrier or trigger cytokine synthesis. Thus, they may affect prenatal brain development. This
inflammatory response may impede brain development, increasing NDD risk (Hsiao and Patterson, 2012).

Neurogenesis involves synapse pruning and maturation by the immune system and microglia. Early-life immune
activation, especially maternal immunological activation (MIA), may hinder the above processes (Sawangchai
et al., 2022). Microglia number and function, synapse maturation, neural circuit reconfiguration, and behavioral
disorders may ensue. These disturbances may also affect postnatal neurodevelopmental processes including
synaptic connections and brain circuits that start certain behaviors.

Thus, rat models of MIA and NDD show how the immune system impairs molecular and brain processes during
key development. For further assessments of MIA's neurobiological effects on NDDs, see Bergdolt and
Dunaevsky (2019), Knuesel et al. (2014), and Estes and McAllister (2016). Some of these models study how
maternal illness or immune challenge cytokines affect offspring brains and behavior.

Pregnancy immune system: Cytokines without infection

Although rigorous immune system management is necessary, immune activation must be strong enough to
prevent or eradicate illness. Genetics and illnesses affect immune system function. COVID-19, also known as
severe acute respiratory syndrome coronavirus 2, affects people differently. Strong immune responses, high
cytokine production, and little symptoms enhance the risk of severe respiratory distress (Cummings et al., 2020).
Women with hypersensitive immune systems that raise cytokine and T-cell counts are more likely to develop
autoimmune disorders (Klein and Schwarz, 2018). Klein, Flanagan (2016). The immune system is vulnerable to
several factors that might affect the developing fetus' risk of non-communicable disease (NDD) during
pregnancy and sickness.

When studying MIA and NDDs, developmental neuroimmunologists may neglect a crucial immune system shift
during pregnancy. Immunosuppression protects non-self fetuses from mother's immune system throughout
pregnancy. Thus, even a little disturbance in pregnancy's immunosuppressive effects might lead to an early
termination. In late pregnancy, immunological changes may cause more severe infections, yet many women see
a temporary improvement in autoimmune illnesses. Rodent models show immunosuppression throughout
pregnancy. Compared to lactating or unbred female rats, pregnant rats show a reduced fever response to low
concentrations of lipopolysaccharide (LPS) (25 μg/kg) at 96 and 24 hours before and after parturition. Most
expecting rodent mothers were hypothermic and had no temperature within 24 hours before delivery, which
caused 80% of them to die between 3–15 hours of birth (Martin et al., 1995). In a study by Sherer et al. (2017),
mice treated to LPS (100 μg/kg) at E11 (mid-gestation) showed a 12%, 20%, and 30% reduction in IL-1β, IL-6,
and IFN-γ splenic output compared to non-pregnant females. By E22, the day before birth, the mother's spleen
produces almost no cytokines in response to the same LPS dose, demonstrating pregnancy's significant
immunosuppression (Sherer et al., 2017). The placenta and fetal brain show a 4-5-fold rise in IL-1β and IL-6
after LPS-induced MIA at E11, although this decreases by E22, the day before birth (Sherer et al., 2017). To be
healthy during pregnancy, immune system activity must reduce significantly.

A healthy pregnancy exposes the fetus to few immune molecules, yet dysregulated cytokine production can
occur even without sickness. High prenatal cytokine exposure may enhance NDD risk and severity. Human
studies have linked elevated cytokine expression in maternal serum and/or amniotic fluid to non-diagnostic
problems in offspring, even without infection. Under certain conditions, latent inflammatory diseases, immune
function changes, stress-induced immunological activation, or minor adjustments to pregnancy-associated
immunosuppression may increase cytokine production and the risk of NDD. Future basic and epidemiological
studies should consider this.

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Immune-activated rodent models for neurodevelopmental disorders
Research conducted on humans cannot definitively establish a causal relationship between risk factors and
NDD. The difficulty in comprehending the development of the disorder arises from the constraints on the
information obtained after death and the inability of existing neuroimaging technology to accurately evaluate the
structural and functional abnormalities in the brain at the cellular or molecular scale. Hence, in order to
investigate the impact of immunological activity and the immune system on neurodevelopment, it is necessary
to utilize animal models.

Researchers utilize mice models to mimic a disease by altering a genetic risk factor. NDD-specific models may
overlook specific symptoms and the complexity of the disorder (Vigli et al., 2020). Contemporary animal
models investigate the common phenotypic characteristics of several disorders, rather than focusing on just one.
This technique aligns with Section 2 of the NIMH RDoC initiative. The presence of overlapping symptoms
between NDD and other disorders suggests potential neurological similarities (Conradt et al., 2021; Auerbach,
2022). Animal models often utilize MIA alone to study the correlation between immune system disturbances,
which are a risk factor for neurodevelopmental disorders (NDDs), and impairments in cognition, social
interaction, and sleep. In order to comprehend the effects of MIA on brain systems, particularly the
inflammatory response in both the mother's body and fetal compartments, as well as the resulting repercussions
connected to neurodevelopmental disorders (NDD) in children, it is imperative to utilize rodent models.

Additionally, it is understood that neurodevelopmental disorders (NDDs) can arise as a result of both
environmental and genetic factors. In order to investigate issues related to neurodevelopmental disorders
(NDD), scientists are combining several factors that induce inflammation, such as genetic mutations,
immunological challenges, nutritional alterations, social stresses, etc., through the utilization of "two-hit" and
"multi-hit" neurodevelopmental models. Utilizing genetic models of "specific disorders" that integrate NDD risk
variables might enhance our comprehension of the interplay between biology and environment in the
development of such illness. Harvey and Boksa (2012) state that a risk factor can lead to many
neurodevelopmental disorders (NDDs) either by having features (such as dosage, timing, immunogenic target,
etc.) that contribute to diverse NDD phenotypes, or by interacting with other susceptibility factors to produce
different NDDs. It is important to examine this aspect while evaluating the fundamental biology of MIA
research models and their conclusions. The following section will discuss the suitability of academics' MIA
models for analyzing data on human epidemiology.

Inflammation and stress during pregnancy

Extensive research has shown a link between stress experienced during pregnancy and various non-verbal
developmental disorders (NDDs) including schizophrenia, autism, and ADHD (Ronald et al., 2011; Diz-Chaves
et al., 2012, 2013; Chan et al., 2018; Minakova and Warner, 2018; Makris et al., 2022). Recent study has utilized
the term "changes in inflammatory biomarkers in the mother's bloodstream," which might potentially heighten
the likelihood of different neurodevelopmental disorders (NDDs), to describe this connection. Miller et al.
(2017) revealed that socioeconomic hardship is a stressor that is linked to increased immunological activation
and hindered development of placental tissue, as shown by transcriptional markers. Immune cells may generate
counterinflammatory-promoting cytokines in response to this stress, as stated by Miller et al. (2017). Stress-
induced alterations in the mother's baseline cortisol levels may potentially impact the likelihood of neural tube
abnormalities (NDDs) in the developing brain. These changes might lead to consistently high or increasing
concentrations of pro-inflammatory cytokines (Van den Bergh et al., 2005).

Animal models of prenatal stress and maternal immune activation (MIA) have shown similar amounts of pro-
inflammatory cytokine production, including IL-6, and activation of microglial cells. Rats born to mothers who
experienced prenatal stress had increased amounts of cytokines in the hippocampus and a higher overall number
of immunoreactive microglial cells, in comparison to unstressed rats. As a result, this caused a stronger
inflammatory reaction to lipopolysaccharide (LPS) in the offspring (Diz-Chaves et al., 2012). Additional
evidence has surfaced that confirms a link between changes in the hypothalamic-pituitary-adrenal (HPA) axis
during pregnancy and the development of anxiety-like behavior, cognitive impairments, and depressive
symptoms in the offspring of stressed rodents and non-human primates (Weinstock, 2005; Weinstock, 2008).
Gestational stress and elevated corticosterone levels in both the mother and the newborn can lead to an increase
in the activity of corticotropin-releasing hormone (CRH) in the amygdala. The disturbance in the feedback
modulation of the HPA axis can continue throughout adulthood (Van den Bergh et al., 2005; Weinstock, 2005;
Weinstock, 2008). Prolonged maternal stress during pregnancy, along with increased levels of cortisol and CRH,
might potentially hinder the developing brain's ability to handle future stresses, immune system problems, or
maternal immune activation (MIA).

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The presence of unforeseen pressures in animal models is frequently disregarded or unreported, despite its
potential to worsen the neurological and behavioral outcomes for both the mother and her children in
conjunction with MIA. In addition to what has been discussed, several factors such as environmental stress
caused by construction, levels of background noise, accommodation, administration of substances, assessment
of behavior, and circumstances of housing may often impact an experiment. Researchers must prioritize
minimizing the impact of external pressures when conducting their work. However, if this is not achievable,
they should meticulously record and provide detailed explanations of these aspects in their findings.

Instigator or protector: the placenta?

The placenta shields the baby from pathogens while providing nutrition and oxygen. Larger immunogenic
molecules and most infectious agents are blocked from passing through the placenta, although there is some
evidence that the placenta actively transfers immune molecules from the mother to the developing foetus
through the circulation (Robbins and Bakardjiev, 2012). Regrettably, not much is known about the placenta
entry of cytokines linked to MIA. Nonetheless, it's crucial to comprehend how the placenta transfers cytokines
during MIA.

Research conducted several decades ago revealed that concordant monozygotic twins for schizophrenia had an
increased chance of monochorionic deliveries (Davis et al., 1995). Benirschke (1990) proposes a four-layer
separating membrane, one for each twin, in conjoined twin pregnancies. In this configuration, the two fetuses
can circulate together. In that case, the mother could expose the twins to additional chemicals and cytokines.
Maternal blood is able to cover the epithelial layer of placental cells during uterine implantation thanks to
interactions between maternal immune and endothelial cells and extravillous fetal cells.

It's possible that syncytiotrophoblasts will shield the placenta from infection. When there are active innate
immune receptors, they can also start cytokine reactions. Because they are hemochorial, rat and human placental
buffers function similarly. The trophoblast epithelium of the rat placenta is immediately submerged in maternal
blood, much like in humans, according to research by Furukawa et al. (2019). This occurs in the decidua, the
human uterine implantation site, since it has a single dividing layer (syncytiotrophoblasts). But the three layers
in this rat could suggest that the fetal-maternal exchange mechanisms are different in the two species. Uterine
natural killer (NK) cells in certain placenta regions aid in the fetus's ability to adapt and adjust during pregnancy
in both species. Poly I:C MIA in rats has been shown to boost placental maternally-derived IL-6 protein (Hsiao
and Patterson, 2011). This causes the placenta to release acute phase immune genes, some of which enter the
fetal blood, and activates the JAK/STAT3 pathway. IL-6 is produced during pregnancy in both the mother and
the child (Zaretsky et al., 2004). It is still unclear how MIA stimulates fetal immune cells. According to certain
studies, LPS and other immunogenic substances are unable to pass through the placental barrier (Ashdown et al.,
2006; Ning, 2008). Additionally, the placenta may trigger an immune reaction. Rats' placental barriers and their
capacity to transfer immunological substances from the mother's circulation hence require more investigation.

According to early research, there was a lower incidence of concordance for multiple NDDs in dichorionic
monozygotic twins (Davis et al., 1995). Since every mouse pup has a distinct placenta, their reactions to MIA
may vary. Placentas are able to transmit hormones since mother's blood passes through them. Blood travels
caudally to distally, or from the cervix to the ovaries, in pregnant rats. After the cervical end fetus, fetuses at
various uterine regions get maternal blood flow. In animals with repeated pregnancies, Ryan and Vandenbergh
(2002) demonstrated that the mother's intrauterine position impacts fetal growth. According to Ryan and
Vandenbergh's (2002) research, the morphological, physiological, and behavioral characteristics of female
fetuses born after male fetuses were masculinized. Hormone imbalances and anomalies in the endocrine system
are involved. A male fetus's amniotic fluid and the mother's circulation allow testosterone to distribute to its
intrauterine neighbors. Depending on the position of the uterus, this transmission route may expose fetuses to
MIA-associated substances at varying rates. This also holds true for immune substances such as cytokines.
Caudal babies in MIA models receive maternal blood flow first and may be more exposed to immunological
components circulating in the pregnant dam.

The placenta's influence on fetal response and the inflammatory consequences of MIA require further
investigation. Researchers should take into account the differences between human and rodent pregnancies
before extrapolating their findings to human NDDs or rat MIA models. This includes the number of fetuses, the
properties of the placental barrier, and the transmission or production of cytokines and immunogens.

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Conclusion
During Maternal Immune Activation (MIA), there are a number of potential factors that could influence fetal
development and the progression of neurodevelopmental disorders. This concludes the examination at hand.
According to our research, it is not mandatory for all studies to incorporate each of these criteria in their
investigations. It is crucial to take into account these factors when analyzing and interpreting the findings of
critical research studies concerning the impact of MIA on NDDs. In an effort to standardize animal models of
maternal immune activation (MIA), increase transparency regarding the variation of parameters across
laboratories, and improve the reproducibility of results across labs, Kentner et al. (2019) have formulated a set
of reporting standards for MIA. While there might be some divergence in the research pertaining to the factors
we have taken into account, this divergence is comparable to what is observed in the behavioral symptoms and
risk factors associated with NDDs in humans. Further research is required to fully understand the
comprehensive effects of these factors, their interaction with perinatal immune activation (specifically the
intensity and duration of the MIA response), and their contributions to the development of the neurological and
behavioral characteristics associated with NDDs.

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